Androgen action is the result of a physiologically complex sequence that is ultimately controlled by opposing pathways of steroid biosynthesis and catabolism. For decades it was assumed that the testicular secretory product, testosterone, is the predominant androgen, but now it is widely recognized that this C19-steroid is an androgenic precursor, the product of incomplete steroidogenic pathways that lead to the ultimate hormonal signals. An array of physiological and pathological studies have shown that testosterone, secreted by the testes and ovary (or peripherally synthesized from androstenedione secreted by the ovary) and in primates, the adrenal, is converted by target tissues into the active androgen, 5a-dihydrotestosterone (DHT)(1,2). The 5α-reductase type 2 enzyme produces the active androgen by converting testosterone, a Δ4-3-ketone, into the corresponding 5a-reduced steroid. Circulating testosterone and androstenedione also serve as precursors of the estrogens through their conversion to estradiol (E2) and estrone by the aromatase enzyme present in many tissues, especially fat (3). Thus, regardless of gender, these secreted C19-Δ4-3-ketosteroids are converted peripherally into divergent signals for 2 different members of the steroid hormone nuclear receptor family. Because of ovarian secretion, estrogens are generally associated with females, and because of testicular secretion, androgens are associated with males. In actuality, each plays a key role in both sexes. As one example, the requirement for estrogens in bone maturation and mineralization in males was demonstrated in an estrogen resistant man having a mutated estrogen receptor (ER) alpha (4). Androgens are known to play important physiological roles in women, and an androgen deficiency syndrome in women is recognized as an important clinical syndrome, involving defects in bone remodeling, sexual function and quality of life (5).
While there are obvious important physiological requirements for androgens in both men and women, there are a number of syndromes in which pathological overproduction of androgens occurs, either in steroidogenic organs or in target tissues. Perhaps the best known is the adrenogenital syndrome, principally the 21-hydroxylase deficiency, which leads to an overproduction of androgen from the adrenal. Some forms of this syndrome are expressed only subtlety (non-classical) leading to milder forms of late onset androgenization (hirsutism, acne) (6). The most prevalent disorder of androgen excess in women is polycystic ovarian syndrome (PCOS) which affects over 5% of reproductive age women (7). Pharmacological intervention varies according to the disorder. The adrenogenital syndrome is treated with dexamethasone which reduces ACTH secretion thereby controlling adrenal androgen synthesis (8). In women, depending upon the source of androgen, hyperandrogenism often responds to oral contraceptives which reduce LH and thereby reduces the stimulation of ovarian androgen secretion, and the estrogenic component of the contraceptive increases sex hormone binding globulin levels which decreases bio-available testosterone. Significant hirsutism is often treated with antiandrogens such as cyproterone acetate, spironolactone or flutamide: cyproterone acetate is a progestin and an antiandrogen that lowers gonadotrophins thus circulating androgens and it inhibits androgen action at the level of the receptor (9); spironolactone is a mineralocorticoid antagonist that is also an androgen receptor antagonist; flutamide is a pure androgen antagonist (10). In addition to antiandrogens, finasteride, the specific inhibitor of the “metabolic activation” of testosterone, is available (11). This compound acts on the 5areductase enzyme type 2, blocking the peripheral conversion of testosterone to DHT in most androgen target organs.
While the availability of this wide array of therapeutic agents makes it possible to treat most forms of hyperandrogenic syndromes, this systemic therapy is not without its pitfalls. For example, in men, antiandrogen therapy with finasteride (Proscar) is common in the treatment of benign prostatic hypertrophy, to prevent progression to prostate cancer. While Proscar is efficacious in decreasing the incidence of low grade prostate cancer, the incidence of high-grade prostate cancers actually increases (12). This called into question the use of antiandrogen therapy to prevent a disorder as serious as prostate cancer. Also questioned is the use of finasteride for the treatment of a much less serious problem; Finasteride, in a formulation called Propecia, is also employed for the treatment baldness. Although Propecia delivers a lower dose of Finasteride than Proscar, it has the same effect on the levels of DHT and testosterone in plasma and prostate (13). This has raised the possibility that this large number of young men who would take Propecia for most of their lives for the treatment of alopecia, might be at increased risk of high-grade prostate cancer (14). As discussed above, interfering with androgen action has clinical ramifications for women as well as men since women also have androgen dependent processes. This is illustrated by androgen replacement therapy becoming a recommended treatment for women with low androgen levels (15). Thus, producing an androgen deficiency syndrome by pharmacological inhibition of androgen action carries significant health risks for both men and women.
While it is apparent that the inhibition of androgen action to treat acne and baldness in men and women, and hirsutism in women, is efficacious, it can carry serious risks. However, this risk may not be necessary since all of these maladies are localized to the skin, an organ that can be treated directly rather than systemically. Systemic androgenic antagonism is not necessary if the antagonist can be applied to, and contained within the skin. Although the skin is an organ that responds to topically applied drugs, it is also permeable to a wide variety of drugs. Thus, many drugs, for example, estrogens, and nicotine, that are applied with skin patches enter the body, circulate in the blood and act systemically (16,17). An antiandrogen developed to act locally, solely within the skin, without systemic action, would alleviate this problem. The design and synthesis of a locally active androgen antagonist to be applied to the skin to treat acne, alopecia, seborrhea, as well as hirsutism is the subject of this application.